nces 2(4.5 months v. 11 months). This temporal profile would becoincident with B-cell repopulation following rituximabtherapy. Furthermore, rituximab is not without its effect onother cell populations. The temporal profile and functional
the site of JCV latency, reactivation leading to CNS infection,the percentage of JCVantibody positive individuals that harborlatent JCVat these sites, and the role of cell mediated immunityin clearing the infection. It is likely that the genesis of PML isLetters to
Reply to Thinking without thinking about natalizumaband PML
We read with interest Ransohoff's Thinking withoutthinking about natalizumab and PML . Besidesnatalizumab, two other monoclonal antibodies directedagainst lymphocyte surface antigens (rituximab and alemtu-zumab) have also been associated with PML. Both are beingstudied as possible treatments for multiple sclerosis, butunlike natalizumab, patients developing PML who had beentreated with these monoclonal antibodies had underlyingdisorders predisposing them to PML. Almost certainly, theexperience obtained with these immunomodulatory agentswill be very helpful in our understanding of the pathogenesisof PML.
Rituximab is a monoclonal antibody directed against CD20expressed by pre-B and B cells, but not stem cells or plasmacells . Rituximab has been associated with PML in 25patientswith lymphoproliferative disorders and systemic lupuserythematosis (FDA). PML has not been reported, as yet, inmultiple sclerosis patients in clinical trials with rituximab[2,3]. Rituximab therapy results in profound B-cell depletion.Reconstitution of the peripheral B-cell population consists ofimmature B cells with delays especially in repopulation ofmemory cells . The rate of B-cell reconstitution varies from6 months to up to 24 months depending on additional anti-lymphocyte treatments, especially stem cell transplantation[5,6]. The observation of PML in the face of treatment with amonoclonal antibody that eradicates the B-cell populationseems to controvert the hypothesis that JCV-infected B cellsbring the infection to the brain. However, in those cases ofPML following rituximab therapy, PML developed at a timewhen B-cell reconstitution would be expected . One study showed that the interval from high-dose therapy withhematopoietic stem cell transplantation for HIV-negativelymphoproliferative disorders to the development of PMLwas longer in those patients who had received rituximab
Journal of the Neurological Scieconsequences of a reduction in T cells in patients treated withrituximab remain unknown. Multiple sclerosis patients, forinstance, treated with rituximab have been demonstrated tohave a reduced CD3 T cells in the CSF .
0022-510X/$ - see front matter 2007 Elsevier B.V. All rights reserved.e Editor
Alemtuzumab, directed against CD52, an antigen expressedby N95% of B and T cells, is most often used in treatment ofmyeloproliferative disorders . PML has been reportedfollowing alemtuzumab in one patient with a myeloprolifera-tive disorder but in none of the relatively of small number ofmultiple sclerosis patients treated with the drug. Alemtuzumabseverely depletes both B and T cells, thus, as with rituximab,possibly removing the JCV-infected B cell. B cells rise to 124%of their baseline values 27months15months after therapy .On the other hand, CD4 cells remain depleted for an average of61 months and CD8 cells for 30 months (Coles CNNS 2004).The low number of PML patients treated with alemtuzumab issurprising given the susceptibility of patients with myelopro-liferative disorders to develop PML. Could the depletion of Bcells protect against PMLby eliminating the cell responsible forcarrying the virus into the brain [10,11]? What about the risk atthe time of B-cell repopulation when the T cells remain low?Any consideration of a role for monoclonal antibody therapiesin the pathogenesis PML must take into account underlyingdiseases, prior therapies and underlying myelo- and immuno-suppression present without monoclonal antibody therapy .With these caveats in mind, will the experience with othermonoclonal antibody therapies certainly add to our under-standing of the pathogenesis of PML? Natalizumab has pro-vided a number of important insights into the pathogenesis ofPML. While other monoclonal antibody therapies beingconsidered for the treatment of multiple sclerosis have alsobeen associated with PML, caution needs to be used in inter-preting the role of these monoclonal antibodies in the patho-genesis of PML. The appearance of PML following rituximabtherapy may be explained by its occurrence at a time of B-cellrepopulation, but that remains to be determined. The extremelylow frequency of PML with alemtuzumab is somewhat para-doxical as B-cell numbers return well before recovery of the Tcell populations. The possible development of PML inmultiplesclerosis patients treated with these agents emphasizes the needfor a better understanding of the pathogenesis of PML including
64 (2008) 198199www.elsevier.com/locate/jnscomplex with contributions by JCV-infected B cells as well asby impaired immune surveillance by JCV-specific cytotoxiclymphocytes. The development of JCV-specific cellularimmunity correlateswith prolonged survival andmilder disease
in patients with PML [12,13]. To borrow from Albert Einstein,
antibody therapy is not likely to be a simple affair.
Response to Letter to the Editor
Dear Dr. Lisak,
This letter in response to my article (doi.10.1016/jns.2006.04.011) in Journal of Neurological Sciences ismost welcome and highly informative. As elegantly pre-sented by the authors, progressive multifocal leukoencepha-lopathy (PML) has emerged in several populations treatedwith monoclonal antibodies. In each case, special circum-stances may have been at play. In patients receiving rituximabfor SLE, it seems plausible that the underlying disease playeda part, as our literature review of 36 cases of PML inrheumatic disease disclosed that 23 cases were diagnosedwith systemic lupus erythematosus (SLE), a ratio far inexcess of that expected by their representation in the casemix. Some SLE/PML were receiving only modest immuno-modulatory therapy at the onset of their neurological disease. It is now appropriate to consider whether each of theclinical scenarios discussed by the authors will represent aunique experiment of nature-plus-therapeutics, and whetherunifying insights that advance our understanding of PML canbe adduced. The authors point us in the right direction bystating the case so clearly.
Sincerely,Richard M. Ransohoff
 Calabrese LH, Molloy ES, Huang D, Ransohoff RM. Progressivemultifocal leukoencephalopathy in rheumatic diseases: evolving clinicaland pathologic patterns of disease. Arthritis Rheum Jul 2007;56(7):211628.
Richard M. RansohoffNeuroinflammation Research Center, Neurosciences,
Cleveland Clinic, 9500 Euclid Ave., NC30,Cleveland, OH 44195, USA
Tel.: +1 216 444 0627; fax: +1 216 444 7927.E-mail address: email@example.com.
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